Abstract

Severe asthma (SA) remains a poorly controlled disease despite use of high doses of systemic corticosteroids (CS) although mild-moderate asthma (MMA) is responsive to low dose inhaled CS. This suggests that SA cannot be solely orchestrated by Th2 cells, which are dominant in milder disease. Analysis of broncholalveolar lavage cells isolated from MMA and SA patients revealed a significantly greater IFN-γ (Th1) immune response in the airways of severe asthmatics with lower Th2 and IL-17 responses. We modeled this complex immune response seen in human SA in mice including poor response to CS. Ifng-/- mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. However, Il17ra-/- mice did not show any reduction in AHR although the mice displayed lower airway inflammation. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells and an inverse correlation between IFN-γ and SLPI expression was detected in SA. Forced expression of SLPI in mice subjected to the SA model decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Taken together, our study has identified a distinct immune response in SA highlighting a dysregulated IFN-γ-SLPI axis that impacts lung function.